IgM from common variable immunodeficiency patients narrowly recognizes erythrocyte and platelet glycans

Autoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of disease-causing autoantibodies in this patient population are unclear. Herein, we report that erythrocytes and platelets from CVID patients with AICs (CVID+AIC) are coated with autoreactive IgM. Glycan array-based analyses of CVID+AIC plasma IgM revealed narrow reactivities to erythrocytic I/i antigens and platelet expressed I/i antigen-related glycans but starkly lower binding to hundreds of other pathogen and tumor-associated carbohydrates. Polyclonal B-cell receptors with corresponding I/i antigen reactivities were highly enriched among CVID+AIC circulating marginal zone (MZ) B cells. Within secondary lymphoid tissues, MZ B cells secreted copious IgM when activated by IL-10 secreting FOXP3-CD25hiTfh cells. In lymph nodes from immunocompetent controls, MZ B cells localized outside of GCs near rare FOXP3-CD25+ cells and plentiful FOXP3+ regulatory T cells. In CVID+AIC lymph nodes, counterpart cells localized to similar anatomic positions but CD25hiTfh cells greatly outnumbered regulatory T cells. In total, our findings indicate glycan-reactive IgM autoantibodies produced outside of GC borders may contribute to the autoimmune pathogenesis of CVID. Comparative gene expression profiling analysis of RNA-seq data for FACS-isolated tonsillar GC B cells and marginal zone B cells